Highly specific ubiquitin-competing molecules effectively promote frataxin accumulation and partially rescue the aconitase defect in Friedreich ataxia cells
Friedreich ataxia is an inherited neurodegenerative disease that leads to progressive disability. There is currently no effective treatment and patients die prematurely. The underlying genetic defect leads to reduced expression of the mitochondrial protein frataxin. Frataxin insufficiency causes mit...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2015-03-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996114003829 |
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doaj-623ff819dad64fa8a418bd9fa45633cc |
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Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Alessandra Rufini Francesca Cavallo Ivano Condò Silvia Fortuni Gabriella De Martino Ottaviano Incani Almerinda Di Venere Monica Benini Damiano Sergio Massaro Gaetano Arcuri Dario Serio Florence Malisan Roberto Testi |
| spellingShingle |
Alessandra Rufini Francesca Cavallo Ivano Condò Silvia Fortuni Gabriella De Martino Ottaviano Incani Almerinda Di Venere Monica Benini Damiano Sergio Massaro Gaetano Arcuri Dario Serio Florence Malisan Roberto Testi Highly specific ubiquitin-competing molecules effectively promote frataxin accumulation and partially rescue the aconitase defect in Friedreich ataxia cells Neurobiology of Disease Friedreich ataxia Frataxin Ubiquitin Orphan drug development |
| author_facet |
Alessandra Rufini Francesca Cavallo Ivano Condò Silvia Fortuni Gabriella De Martino Ottaviano Incani Almerinda Di Venere Monica Benini Damiano Sergio Massaro Gaetano Arcuri Dario Serio Florence Malisan Roberto Testi |
| author_sort |
Alessandra Rufini |
| title |
Highly specific ubiquitin-competing molecules effectively promote frataxin accumulation and partially rescue the aconitase defect in Friedreich ataxia cells |
| title_short |
Highly specific ubiquitin-competing molecules effectively promote frataxin accumulation and partially rescue the aconitase defect in Friedreich ataxia cells |
| title_full |
Highly specific ubiquitin-competing molecules effectively promote frataxin accumulation and partially rescue the aconitase defect in Friedreich ataxia cells |
| title_fullStr |
Highly specific ubiquitin-competing molecules effectively promote frataxin accumulation and partially rescue the aconitase defect in Friedreich ataxia cells |
| title_full_unstemmed |
Highly specific ubiquitin-competing molecules effectively promote frataxin accumulation and partially rescue the aconitase defect in Friedreich ataxia cells |
| title_sort |
highly specific ubiquitin-competing molecules effectively promote frataxin accumulation and partially rescue the aconitase defect in friedreich ataxia cells |
| publisher |
Elsevier |
| series |
Neurobiology of Disease |
| issn |
1095-953X |
| publishDate |
2015-03-01 |
| description |
Friedreich ataxia is an inherited neurodegenerative disease that leads to progressive disability. There is currently no effective treatment and patients die prematurely. The underlying genetic defect leads to reduced expression of the mitochondrial protein frataxin. Frataxin insufficiency causes mitochondrial dysfunction and ultimately cell death, particularly in peripheral sensory ganglia. There is an inverse correlation between the amount of residual frataxin and the severity of disease progression; therefore, therapeutic approaches aiming at increasing frataxin levels are expected to improve patients' conditions. We previously discovered that a significant amount of frataxin precursor is degraded by the ubiquitin/proteasome system before its functional mitochondrial maturation. We also provided evidence for the therapeutic potential of small molecules that increase frataxin levels by docking on the frataxin ubiquitination site, thus preventing frataxin ubiquitination and degradation. We called these compounds ubiquitin-competing molecules (UCM). By extending our search for effective UCM, we identified a set of new and more potent compounds that more efficiently promote frataxin accumulation. Here we show that these compounds directly interact with frataxin and prevent its ubiquitination. Interestingly, these UCM are not effective on the ubiquitin-resistant frataxin mutant, indicating their specific action on preventing frataxin ubiquitination. Most importantly, these compounds are able to promote frataxin accumulation and aconitase rescue in cells derived from patients, strongly supporting their therapeutic potential. |
| topic |
Friedreich ataxia Frataxin Ubiquitin Orphan drug development |
| url |
http://www.sciencedirect.com/science/article/pii/S0969996114003829 |
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doaj-623ff819dad64fa8a418bd9fa45633cc2021-03-22T12:42:21ZengElsevierNeurobiology of Disease1095-953X2015-03-01759199Highly specific ubiquitin-competing molecules effectively promote frataxin accumulation and partially rescue the aconitase defect in Friedreich ataxia cellsAlessandra Rufini0Francesca Cavallo1Ivano Condò2Silvia Fortuni3Gabriella De Martino4Ottaviano Incani5Almerinda Di Venere6Monica Benini7Damiano Sergio Massaro8Gaetano Arcuri9Dario Serio10Florence Malisan11Roberto Testi12Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome “Tor Vergata,” Via Montpellier 1, Rome 00133, Italy; Fratagene Therapeutics Ltd., 22 Northumberland Rd., Dublin, IrelandLaboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome “Tor Vergata,” Via Montpellier 1, Rome 00133, ItalyLaboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome “Tor Vergata,” Via Montpellier 1, Rome 00133, ItalyLaboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome “Tor Vergata,” Via Montpellier 1, Rome 00133, Italy; Fratagene Therapeutics Ltd., 22 Northumberland Rd., Dublin, IrelandLaboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome “Tor Vergata,” Via Montpellier 1, Rome 00133, ItalyLaboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome “Tor Vergata,” Via Montpellier 1, Rome 00133, ItalyDepartment of Experimental Medicine and Surgery, University of Rome “Tor Vergata,” Via Montpellier 1, Rome 00133, ItalyLaboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome “Tor Vergata,” Via Montpellier 1, Rome 00133, ItalyLaboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome “Tor Vergata,” Via Montpellier 1, Rome 00133, ItalyLaboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome “Tor Vergata,” Via Montpellier 1, Rome 00133, ItalyLaboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome “Tor Vergata,” Via Montpellier 1, Rome 00133, ItalyLaboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome “Tor Vergata,” Via Montpellier 1, Rome 00133, ItalyLaboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome “Tor Vergata,” Via Montpellier 1, Rome 00133, Italy; Fratagene Therapeutics Ltd., 22 Northumberland Rd., Dublin, Ireland; Corresponding author at: Laboratory of Signal Transduction, University of Rome “Tor Vergata,” Via Montpellier 1, 00133, Rome, Italy.Friedreich ataxia is an inherited neurodegenerative disease that leads to progressive disability. There is currently no effective treatment and patients die prematurely. The underlying genetic defect leads to reduced expression of the mitochondrial protein frataxin. Frataxin insufficiency causes mitochondrial dysfunction and ultimately cell death, particularly in peripheral sensory ganglia. There is an inverse correlation between the amount of residual frataxin and the severity of disease progression; therefore, therapeutic approaches aiming at increasing frataxin levels are expected to improve patients' conditions. We previously discovered that a significant amount of frataxin precursor is degraded by the ubiquitin/proteasome system before its functional mitochondrial maturation. We also provided evidence for the therapeutic potential of small molecules that increase frataxin levels by docking on the frataxin ubiquitination site, thus preventing frataxin ubiquitination and degradation. We called these compounds ubiquitin-competing molecules (UCM). By extending our search for effective UCM, we identified a set of new and more potent compounds that more efficiently promote frataxin accumulation. Here we show that these compounds directly interact with frataxin and prevent its ubiquitination. Interestingly, these UCM are not effective on the ubiquitin-resistant frataxin mutant, indicating their specific action on preventing frataxin ubiquitination. Most importantly, these compounds are able to promote frataxin accumulation and aconitase rescue in cells derived from patients, strongly supporting their therapeutic potential.http://www.sciencedirect.com/science/article/pii/S0969996114003829Friedreich ataxiaFrataxinUbiquitinOrphan drug development |